Diabetes is a chronic, life-threatening disease for which there is no known cure. It is a syndrome characterized by hyperglycemia and relative insulin deficiency. Diabetes affects more than 120 million people world wide, and is projected to affect more than 220 million people by the year 2020. It is estimated that one out of every three children today will develop diabetes sometime during their lifetime. Diabetes is usually irreversible, and can lead to a variety of severe health complications, including coronary artery disease, peripheral vascular disease, blindness and stroke. The Center for Disease Control (CDC) has reported that there is a strong association between being overweight, obesity, diabetes, high blood pressure, high cholesterol, asthma and arthritis. Individuals with a body mass index of 40 or higher are more than 7 times more likely to be diagnosed with diabetes.
There are two main types of diabetes: Type I diabetes (insulin-dependent diabetes mellitus) and Type II diabetes (non-insulin-dependent diabetes mellitus). Varying degrees of insulin secretory failure may be present in both forms of diabetes. In some instances, diabetes is also characterized by insulin resistance. Insulin is the key hormone used in the storage and release of energy from food.
As food is digested, carbohydrates are converted to glucose and glucose is absorbed into the blood stream primarily in the intestines. Excess glucose in the blood, e.g., following a meal, can stimulate insulin secretion, which can promote entry of glucose into the cells, and which controls the rate of metabolism of most carbohydrates.
Insulin secretion functions to control the level of blood glucose both during fasting and after a meal, to keep the glucose levels at an optimum level. In a person without diabetes, blood glucose levels are typically between 80 and 90 mg/dL of blood during fasting and between 120 to 140 mg/dL during the first hour or so following a meal. For a person with diabetes, the insulin response does not function properly (either due to inadequate levels of insulin production or insulin resistance), resulting in blood glucose levels below 80 mg/dL during fasting and well above 140 mg/dL after a meal.
Currently, persons suffering from diabetes have limited options for treatment, including taking insulin orally or by injection. In some instances, controlling weight and diet can impact the amount of insulin required, particularly for non-insulin dependent diabetics. Monitoring blood glucose levels is an important process that is used to help diabetics maintain blood glucose levels as near as normal as possible throughout the day.
Self administration of insulin is not only inconvenient but also associated with significant morbidity and other safety concerns. Hence transplant of insulin producing beta cells in the pancreas has been attempted as a form of therapy, but with less success due to limited supply and long term need for immunosuppression. Recently, transplantation of autologous stem cells (mesenchymal, bone marrow, and others) have been proposed to increase/replace the supply of insulin. Early results are encouraging, especially in Type II diabetes where auto-immune reaction against these cells appears limited.
Nevertheless, to date uniformity in the best method for transplanting such cells has not been reached. Various methods that have been applied include, for example, transplanting the cells surgically in the sub capsular space in the kidney, the liver, and non selective systemic injection both intravenously and intra-arterially, with the hope of “homing” these cells to the pancreatic tissue, to allow engraftment.
The long term success of any approach for delivering transplanted cells will be dependent on the ability of these cells to differentiate into functioning beta cells in the pancreas, and allowing their survival in a supporting milieu. There are numerous reports that suggest the pancreas itself is the best target for the transplanted cells to meet both of these objectives. So far efforts have included sub-selective endovascular injection of these cells into the arterial supply of the pancreatic tissue. Such an approach is subject to significant variation in the number of cells actually introduced to the pancreas (versus other organs in the same vascular bed including the spleen, the liver and the stomach). Furthermore, safety issues have been raised/reported when these cells were inadvertently targeted to other organs. How to best achieve successful engraftment of these cells into the pancreatic tissue is presently a limitation of some of these early studies; even though long term success of the technique appears to be directly correlated with the efficiency of the engraftment.
The present state of the art would benefit from a method where these cells can be targeted selectively to the pancreas, where efficient and safe engraftment can be achieved, especially to the pancreatic tail, where a large number of the endogenous islet cells reside, and devices and kits that are adapted to enable such methods.
In another disease process involving the pancreas, pancreatic cancer is the fourth leading cause of death from cancer, with 47,000 new cases diagnosed in the United States every year. At the time of diagnosis, only twenty percent of the patients suffering from pancreatic cancer present with localized disease amenable to surgery. Forty percent of the patients present with locally advanced (and therefore unresectable) disease, and another forty percent from distal metastasis. Pancreatic cancer is considered an almost chemoresistant tumor. The average tumor response rate with 5-FU alone, or in combination with other agents, is in the range of 7%-28%; as such systemic adjuvant chemotherapy for pancreatic cancer has not increased the 5 year survival rate. The ineffectiveness of systemic chemotherapy is at least in part due to failure to reach a drug concentration within the tumor because of dose limited toxicity in bone marrow and epithelial tissue. Since systemic chemotherapy is of limited effectiveness, approaches beyond systemic chemotherapy are needed for advanced pancreatic cancer. One promising approach is local intra-arterial delivery. In other cancers, intra-arterial chemotherapy has improved the response rates and quality of life in patients with liver metastasis and colorectal cancer.
Intra-arterial infusion allows higher drug concentration to reach the tumor, overcoming the problem of poor blood flow to tumor mass in comparison to healthy tissue. Furthermore, intra-arterial chemotherapy can also take advantage of the first pass effect of chemotherapeutics, generating higher level drug concentrations at the tumor cell membrane and therefore enhancing cellular drug uptake as compared to intravenous infusion. Lastly, local delivery can reduce systemic side effects.
The chemotherapy is usually given through catheters placed in the celiac/hepatic artery or portal vein. However, one of the major unresolved issues in pancreatic arterial infusion chemotherapy remains the optimal method of catheter placement. In fact, the tumor response rates of pancreatic arterial infusion chemotherapy can range widely, for example, from 7% to 65%, at least in part due to efficacy of drug delivery where anticancer drugs were administered via the celiac artery without assessment of drug distribution. A key issue in catheter localization is the redundant nature of blood supply to the pancreas overlapping adjacent organs. Furthermore, the small size and anatomical variability of the branches of the hepatic and splenic arteries to the pancreas precludes reproducible cannulation via interventional techniques.
A need exists for a device and method whereby biologics (i.e., chemotherapy) can selectively be targeted to the pancreas, where the therapeutic index of a drug can be enhanced by increasing local tissue concentration, with minimal dosing to the surrounding organ.